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Drug resistance in colon cancer
1Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Abstract:
A significant obstacle for the successful management of patients with colorectal cancer is intrinsic drug resistance or, in patients who respond to chemotherapy, acquired drug resistance. Drug resistance can occur through a variety of mechanisms, including alterations in drug influx, drug efflux, intracellular metabolic activation, and intracellular catabolism, or through alterations in the drug's target. In addition, alterations in genes involved in the regulation of the cell cycle or in DNA damage repair may result in a cell becoming resistant to chemotherapy. In this chapter, the mechanisms of action and the mechanisms of resistance to the fluoropyrimidines and raltitrexed (Tomudex; Zeneca Pharmaceuticals, Wilmington, DE) are reviewed, focusing on newer studies using gastric and colorectal tumor samples obtained from patients. Clinical trials using this new information are anticipated.
Insights
Drug resistance in colorectal cancer management is a major challenge. Understanding resistance mechanisms to chemotherapy, like fluoropyrimidines, is key to developing new treatments.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Intrinsic and acquired drug resistance significantly impede colorectal cancer treatment success.
- Mechanisms of resistance involve altered drug transport, metabolism, target modification, cell cycle regulation, and DNA repair pathways.
Purpose of the Study:
- To review the mechanisms of action and resistance for fluoropyrimidines and raltitrexed in colorectal cancer.
- To highlight recent studies utilizing patient-derived tumor samples to elucidate these resistance mechanisms.
Main Methods:
- Review of existing literature on fluoropyrimidine and raltitrexed mechanisms.
- Analysis of studies focusing on colorectal and gastric tumor samples from patients.
- Examination of genetic alterations related to drug resistance.
Main Results:
- Drug resistance in colorectal cancer is multifactorial, involving cellular and molecular changes.
- Specific alterations in drug influx, efflux, metabolism, target, cell cycle, and DNA repair contribute to resistance.
- Recent research provides insights into these mechanisms using clinical tumor samples.
Conclusions:
- A comprehensive understanding of drug resistance mechanisms is crucial for improving colorectal cancer therapy.
- Future clinical trials are expected to leverage this knowledge for more effective treatment strategies.
- Targeting specific resistance pathways may overcome chemotherapy failure in colorectal cancer patients.